Nedisertib and Radiation Therapy, Followed by Temozolomide for the Treatment of Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma or Gliosarcoma

• ClinicalTrials.gov Identifier: NCT04555577
• Recruitment Status: Recruiting
• First Posted: September 18, 2020
• Last Update Posted: February 21, 2022
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

This phase I trial investigates the side effects and best dose of nedisertib, and to see how well it works in combination with radiation therapy in treating patients with newly diagnosed MGMT unmethylated glioblastoma or gliosarcoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Nedisertib may further stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nedisertib with radiation therapy may work better than radiation therapy alone in treating patients with glioblastoma or gliosarcoma.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Gliosarcoma	Drug: Nedisertib; Radiation: Radiation Therapy; Procedure: Resection; Drug: Temozolomide	Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of nedisertib (M3814) in combination with standard of care radiation dose (60 Gy, 2 Gy/fraction over 6 weeks) in patients with newly diagnosed MGMT unmethylated glioblastoma (GBM). (Stage I) II. To determine the ability of M3814 to cross the blood brain barrier and to evaluate their pharmacodynamic properties in resected tissue. (Stage II)

SECONDARY AND EXPLORATORY OBJECTIVES:

I. To evaluate the dose limiting toxicities (DLT). (Stage I) (Secondary Objective) II. To determine the overall response rate (ORR), median progression free survival (mPFS) and median overall survival (mOS) of M3814 in combination with radiation. (Stage I) (Secondary Objective) II. To determine the overall response rate (ORR), median progression free survival (mPFS) and median overall survival (mOS) of M3814 in combination with radiation. (Stage II) (Exploratory Objective)

CORRELATIVE OBJECTIVES:

I. To evaluate pharmacodynamic properties of M3814. II. To assess the alterations in tumor immune microenvironment as a result of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK) inhibition.

OUTLINE: This is a dose-escalation study of nedisertib. Patients are assigned to 1 of 2 stages.

STAGE I (CONCURRENT): Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive nedisertib orally (PO) on each day of radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

STAGE I (ADJUVANT): Patients receive temozolomide PO once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

STAGE II (CONCURRENT): Patients receive nedisertib and undergo standard of care radiation therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients undergo surgical resection.

STAGE II (ADJUVANT): Patients receive temozolomide as in Stage I.

After completion of study treatment, patients are followed up every 3 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 29 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Trial of DNA-PK Inhibitor (M3814) in Combination With Radiation and Adjuvant Temozolomide in Newly Diagnosed MGMT Unmethylated Glioblastoma
• Actual Study Start Date: September 20, 2020
• Estimated Primary Completion Date: October 30, 2023
• Estimated Study Completion Date: October 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stage I (nedisertib, radiation therapy, temozolomide); CONCURRENT: Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive nedisertib PO on each day of radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.	Drug: Nedisertib; Given PO; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Drug: Temozolomide; Given PO; Other Names: CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac; TMZ
Experimental: Stage II (nedisertib, radiation, temozolomide, surgery); CONCURRENT: Patients receive nedisertib and undergo standard of care radiation therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients undergo surgical resection. ADJUVANT: Patients receive temozolomide as in Stage I.	Drug: Nedisertib; Given PO; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Procedure: Resection; Undergo surgical resection; Other Name: Surgical Resection; Drug: Temozolomide; Given PO; Other Names: CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac; TMZ

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose (MTD) (Stage I) [ Time Frame: Within the first 10 weeks of study treatment ]
   Will employ the Bayesian optimal interval to find the MTD.
2. Ability of nedisertib (M3814) to cross the blood brain barrier (Stage II) [ Time Frame: At 1, 2, and 4 hours after drug administration on fraction day 1 and at pre-dose and 1, 2, and 4 hours after drug administration on fraction day 10 ]
   Ability of the investigational drug to cross the blood brain barrier will be tested by measuring concentration of the drug within the blood and the resected brain tumor tissue. This will be correlated with biomarkers of deoxyribonucleic acid (DNA) damage in brain tumor tissue, blood, and hair follicle.

Secondary Outcome Measures :

1. Dose-limiting toxicities (DLT) (Stage I) [ Time Frame: Within the first 10 weeks of study treatment ]
   A DLT is defined as a clinically significant adverse event considered at least possibly related to M3814 in combination with radiation during the first 10 weeks of study treatment (4 weeks after completion of radiation and DNA damage response [DDR] inhibitors) for both stage I and stage II patients.
2. Overall response rate (Stage I) [ Time Frame: Up to 3 years ]
3. Median progression-free survival (Stage I) [ Time Frame: From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years ]
4. Median overall survival (Stage I) [ Time Frame: Up to 3 years ]
5. Overall response rate (Stage II) [ Time Frame: Up to 3 years ]
6. Median progression-free survival (Stage II) [ Time Frame: From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years ]
   Progression-free survival will be evaluated using the Kaplan-Meier product-limit survival curve methodology and will be compared to historical controls. Median progression free survival will be estimated using Kaplan-Meier estimates and associated two-sided 95% confidence intervals.
7. Median overall survival (Stage II) [ Time Frame: Up to 3 years ]
   Overall survival will be evaluated using the Kaplan-Meier product-limit survival curve methodology and will be compared to historical controls.

Other Outcome Measures:

1. Pharmacodynamic properties of M3814 [ Time Frame: Up to 3 years ]
   Blood and hair follicle will be obtained from stage I & II patients during the screening period, on days 8-12 of concurrent radiation and M3814, and on the last day of radiation and at disease progression. Logistic regression will be used to explore the correlations between response rates and correlative markers. Changes in correlative markers over time will be analyzed by Wilcoxon signed rank tests for pairs of times and linear mixed effects models more generally. Data graphs will be generated to visualize data distributions as well as relationships between variables.
2. Alterations in tumor immune microenvironment [ Time Frame: Up to 3 years ]
   Will assess the alterations in tumor immune microenvironment as a result of deoxyribonucleic acid-dependent protein kinase inhibition. Logistic regression will be used to explore the correlations between response rates and correlative markers. Changes in correlative markers over time will be analyzed by Wilcoxon signed rank tests for pairs of times and linear mixed effects models more generally. Data graphs will be generated to visualize data distributions as well as relationships between variables.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed informed consent form (ICF)
• Ability and willingness to comply with the requirement of the study protocol
• Histologically confirmed World Health Organization (WHO) grade IV glioma (GBM) or gliosarcoma, IDH wild-type
• Documentation of MGMT unmethylated GBM per testing at any Clinical Laboratory Improvement Amendment (CLIA) certified laboratory
• Patients must have undergone brain surgery or biopsy and must not have had any further treatments following surgery
• Have Karnofsky performance status (KPS) of >= 60 or Eastern Cooperative Oncology Group (ECOG) =< 2
• A baseline magnetic resonance imaging (MRI) of brain obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids no greater than 4 mg a day of dexamethasone (or equivalent dose of other steroids) for at least 3 days
• Patients must start treatment within 8 weeks of last brain surgical procedure (biopsy or resection)
• Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior to day 1 of the study)
• Platelets >= 100,000/mcL (within 14 days prior to day 1 of the study)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 14 days prior to day 1 of the study)

• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 14 days prior to day 1 of the study)

  • Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN (within 14 days prior to day 1 of the study)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 14 days prior to day 1 of the study)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (within 14 days prior to day 1 of the study)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days prior to day 1 of the study)
• Have provided tissue from an archival tissue sample
• Female subjects of childbearing potential should have a negative serum pregnancy test within 14 days of day 1 of the study

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile

  • Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception during the course of the study
• STAGE I: In the case stage I patients need resection as determined by the treating physicians during or after completion of radiation therapy (RT) and that pathology of resected lesion is not consistent with recurrent GBM, the patient can continue on the study (complete 6 weeks of RT + M3814) if deemed appropriate by the treating physicians. The tissue obtained in such circumstances will be analyzed as in Stage II subjects. However, these cases will not count towards the 5 patients who will be enrolled during Stage II. These patients will contribute to the correlative endpoints detailed above and ORR, OS, and PFS as Stage II patients
• STAGE II: Patients meet above criteria, would benefit from further non-urgent surgical resection of at least one enhancing lesion per the treating physician, and would provide consent to undergo surgery after treatment with RT and M3814

Exclusion Criteria:

• Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery. Prior treatment with Gliadel wafers and laser interstitial thermal therapy (LITT) will be excluded. Active treatment with the tumor treating filed devices such as Optune will be excluded
• Currently participating or previously participated in any other newly diagnosed GBM therapeutic trials
• History of MGMT methylated status performed at any CLIA certified laboratory
• Any serious medical condition that interferes with adherence to study procedures
• Malignancies other than the disease under study within 5 years prior to day 1 of the study, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =< 6, and prostate-specific antigen [PSA] =< 10 mg/mL, etc)
• Has known disease in the posterior fossa, gliomatous meningitis, extracranial disease or multicentric enhancing disease. Multicentric disease is defined as discrete sites of contrast enhancing disease without contiguous T2/fluid-attenuated inversion recovery (FLAIR) abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating physician
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the screening visit
• Contraindication for undergoing MRIs
• Inability to comply with study and follow-up procedures

• Signs or symptoms of infection, received oral or intravenous (IV) antibiotics within 2 weeks prior to day 1 of the study

  • Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
• History of human immunodeficiency virus (HIV) infection
• Administration of a live, attenuated vaccine within 4 weeks before day 1 of the study or anticipation that such a live, attenuated vaccine will be required during the study
• Influenza vaccination can be given. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to day 1 of the study or at any time during the study and for 5 months after completion of adjuvant temozolomide (TMZ)
• History of long QT syndrome
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of M3814 or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Anticipation of need for a major surgical procedure during the course of the study (excluding patients in Stage II with planed non-urgent neuro-surgical resection)
• Subjects at increased risk for radiation toxicities, such as known active collagen vascular disease (example; scleroderma, Sjogren's disease, etc) or other inherited radiation hypersensitivity syndromes (example; Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
• Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions (including pancreas deficiency requiring Creon therapy) that may hamper compliance and/or absorption of M3814
• Patients may not receive concomitant chemotherapy, immunotherapy, or radiotherapy (other than as pertained to standard of care for GBM) while patients are on study
• Prior treatment with DNA damage response inhibitors (including inhibitors of PARP, ATR, WEE)
• Subjects currently receiving or unable to stop using medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A, CYP2C19, CYP2C9 and/or P glycoprotein (P-gp) (CYP and/P-gp must stop at least 1 week before treatment with M3814 for inhibitors and 3 weeks before treatment with M3814 for inducers) or drugs mainly metabolized by CYP3A, CYP2C19, CYP2C9 with a narrow therapeutic index (must stop at least 1 day prior). In addition concomitant use of H2 blockers of proton pump inhibitors (PPIs) is prohibited. Patients must stop H2 blockers and PPIs 4 days prior to the first treatment. Calcium carbonate use is acceptable
• STAGE II: Patients who are status post (s/p) gross total resection with no remaining disease available for resection or tumor remaining in a region of the brain not amenable to resection

Contacts and Locations

Locations

United States, Texas

M D Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Nazanin Majd 713-792-2883 nkmajd@mdanderson.org

Principal Investigator: Nazanin Majd

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Nazanin Majd; M.D. Anderson Cancer Center

More Information

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT04555577
• Other Study ID Numbers: 2019-1035; NCI-2020-04491 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2019-1035 ( Other Identifier: M D Anderson Cancer Center )
• First Posted: September 18, 2020
• Last Update Posted: February 21, 2022
• Last Verified: February 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Glioblastoma; Gliosarcoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Peposertib; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors